Anti-PD1 plus BRAF/MEK inhibitors (triplet therapy) after failure of standard therapy in patients (pts) with advanced melanoma.
Authors: Lisa Zimmer, Florentia Dimitriou, Piyush Grover, Jessica Cecile Hassel, Michael Erdmann, Andrea Forschner, Douglas Buckner Johnson, Elisabeth Livingstone, Alexander Roesch, Selma Ugurel, Carsten Schulz, Carola Berking, Alexander M. Menzies, Georgina V. Long, Reinhard Dummer, Dirk Schadendorf, Lea Jessica Albrecht
Journal: Journal of Clinical Oncology (2023)

9528 Background: Preclinical models support the combination of immune checkpoint inhibitors (ICI) with targeted therapy (TT), suggesting a synergistic effect; however, clinical trials evaluating the efficacy of triplet combination in first-line setting showed limited advantage compared to TT only. Early data from the phase II TRIDeNT (NCT02910700) study showed promising clinical activity in anti-PD1 refractory pts. We sought to evaluate the efficacy of combined TT plus anti-PD1 after the failure of standard therapy in pts with advanced melanoma. Methods: This retrospective, multicenter study included pts with advanced melanoma who were treated with a BRAF inhibitor and a MEK inhibitor in combination with a PD1 inhibitor after failure of a minimum of one standard therapy in seven major melanoma centers between February 2016 and July 2022. Demographics, disease characteristics, therapy details, and outcome data were evaluated. Results: 59 pts were identified; med age was 48 yrs (range, 24-80), 32 pts (54.2%) were males, 20 pts (33.9%) had ECOG PS 1, 46 pts (78%) had 3 or more metastatic sites, 40 pts (67.8%) had brain metastases, and 25 (42.2%) had LDH levels above the upper limit of normal before initiation of triple therapy. Median follow-up time was 16.2 months (IQR, 6.02-20.81). Median number of previous treatment lines was 2 (range, 1-6); 40 pts (67.8%) were pretreated with at least one line of ICI and TT in any sequence. Of 55 pts who received ICI (n = 41 CTLA4 plus PD1; n = 9 PD1 mono; n = 2 CTLA4 mono; n = 3 PD1-based therapy) prior to triplet therapy, 44 pts (80%) were primary resistant (progressive disease (PD); stable disease (SD) for &lt; 6 months), and 11 pts (20%) secondary resistant (complete response (CR), partial response (PR), SD for &gt; 6 months) to the ICI therapy. Treatment with triplet therapy resulted in an overall response rate (ORR) of 44.1% (n = 26) and a disease control rate (DCR) of 55.9% (n = 33) with a median duration of response of 13.7 months (range, 5.4-33.2). Median PFS for the entire cohort was 6 months (95% CI, 3.88-8.08), with a 12-month PFS of 29.4% (95% CI, 17.8-42.1) and a 24-month PFS of 20.2% (95% CI, 11.0-32.8). Median OS was 15.7 months (95% CI, 8.1-23.3 months), with a 12-month OS of 52.7% (95% CI, 39.1-65.7) and a 24-month OS of 43.2% (95% CI, 29.6-55.9). Pts with extracerebral PD prior to triplet therapy (40.7%, n = 24) showed an ORR of 50%, pts with intracerebral PD (32.2%, n = 19) of 47.4%, and pts with global PD (27.1%, N = 16) of 31.3%. Treatment-related adverse events (TRAE) of grade ≥3 occurred in 17 of 59 pts (28.8%), of which cytokine release syndrome (n = 7) and hepatitis (n = 3) were the most common. In 16.9% (n = 10) of pts, TRAEs led to treatment discontinuation. Conclusions: Triple therapy has shown promising efficacy in heavily pretreated pts with advanced melanoma and may represent a treatment option after failure of standard therapy with ICI and TT.